elafin and Cystadenocarcinoma--Serous

High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting.

Topics: bcl-X Protein; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cystadenocarcinoma, Serous; Elafin; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kaplan-Meier Estimate; MAP Kinase Signaling System; MCF-7 Cells; Outcome Assessment, Health Care; Ovarian Neoplasms; Prognosis; Proportional Hazards Models; Proteomics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference

Ovarian cancer is a leading cause of cancer mortality in women. The aim of this study was to elucidate whether whey acidic protein (WAP) genes on chromosome 20q13.12, a region frequently amplified in this cancer, are expressed in serous carcinoma, the most common form of the disease. Herein, we report that a trio of WAP genes (HE4, SLPI, and Elafin) is overexpressed and secreted by serous ovarian carcinomas. To our knowledge, this is the first report linking Elafin to ovarian cancer. Fluorescence in situ hybridization analysis of primary tumors demonstrates genomic gains of the Elafin locus in a majority of cases. In addition, a combination of peptidomimetics, RNA interference, and chromatin immunoprecipitation experiments shows that Elafin expression can be transcriptionally upregulated by inflammatory cytokines through activation of the nuclear factor kappaB pathway. Importantly, using a clinically annotated tissue microarray composed of late-stage, high-grade serous ovarian carcinomas, we show that Elafin expression correlates with poor overall survival. These results, combined with our observation that Elafin is secreted by ovarian tumors and is minimally expressed in normal tissues, suggest that Elafin may serve as a determinant of poor survival in this disease.

Topics: Biomarkers, Tumor; Blotting, Northern; Blotting, Western; Chromatin Immunoprecipitation; Cystadenocarcinoma, Serous; Elafin; Female; Gene Amplification; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Neoplasm Staging; NF-kappa B; Ovarian Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Survival Analysis; Tissue Array Analysis